Symphathetic Nervous System Activation

Surgery stimulates the hypothalamic-pituitary-adrenal (HPA) axis and leads to sympathetic nerve activation, which triggers the release of catecholamines. In addition to their cardiovascular affects (tachycardia, hypertension), these hormones also affect the liver, kidneys, and pancreas.2

Endocrinologic activation

Surgical stress results in a variety of changes in serum levels of endocrinologic hormones.

Epinephrinenorepinephrine, and cortisol levels increase during surgery and remain elevated for 1–3 days. Serum antidiuretic hormone levels may be elevated for up to 1 week postoperatively, which can lead to hyponatremia.

Immunologic activation

  • Immunologic activation occurs with the production of cytokines and acute phase reactants, and resultant neutrophil release and demargination, and lymphocyte proliferation

 

 

  1.  

  2. In many cases, DAMP molecules are sensed by pattern recognition receptors (PRRs), which are the same receptors that cells use to sense invading pathogens. This explains, in part, the similar clinical picture of systemic inflammation observed in injured and/or septic patients.

  3. The central nervous system receives information with regard to injury-induced inflammation via soluble mediators as well as direct neural projections that transmit information to regulatory areas in the brain. The resulting neuroendocrine reflex plays an important modulatory role in the immune response.

  4. Inflammatory signals activate key cellular stress responses (the oxidative stress response, the heat shock protein response, the unfolded protein response, autophagy, and programmed cell death), which serve to mobilize cellular defenses and resources in an attempt to restore homeostasis.

  5. The cells, mediators, signaling mechanisms, and pathways that compose and regulate the systemic inflammatory response are closely networked and tightly regulated by transcriptional events as well as by epigenetic mechanisms, posttranslational modification, and microRNA synthesis.

  6. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients.

  7. Management of critically ill and injured patients is optimized with the use of evidence-based and algorithm-driven therapy.

Inflammatory Response

The inflammatory response to injury or infection occurs as a consequence of the local or systemic release of “pathogen-associated” or “damage-associated” molecules, which use similar signaling pathways to mobilize the necessary resources required for the restoration of homeostasis. Minor host insults result in a localized inflammatory response that is transient and in most cases beneficial.

Major host insults, however, may lead to amplified reactions, resulting in systemic inflammation, remote organ damage, and multiple organ failure in as many as 30% of those who are severely injured.

Recent data support this idea and suggest that severely injured patients who are destined to die from their injuries differ from survivors only in the degree and duration of their dysregulated acute inflammatory response.1,2

This topic is highly relevant because systemic inflammation is a central feature3 of both sepsis and severe trauma. Understanding the complex pathways that regulate local and systemic inflammation is necessary to develop therapies to intervene during overwhelming sepsis or after severe injury. Sepsis, defined by a systemic inflammatory response to infection, is a disease process with an incidence of over 900,000 cases per year. Further, trauma is the leading cause of mortality and morbidity for individuals under age 45.

review what is known about the soluble and cellular effectors of the injury-induced inflammatory response; how the signals are sensed, transduced, and modulated; and how their dysregulation is associated with immune suppression. We will also discuss how these events are monitored and regulated by the central nervous system. Finally, we will review how injury reprograms cellular metabolism, in an attempt to mobilize energy and structural stores to meet the challenge of restoring homeostasis.

 

  1. Endogenous damage-associated molecular patterns (DAMPs) are produced following tissue and cellular injury. These molecules interact with immune and nonimmune cell receptors to initiate a “sterile” systemic inflammatory response following severe traumatic injury. {What is the nature of these molecules}

 

Traumatic injury activates the innate immune system to produce a systemic inflammatory response in an attempt to limit damage and to restore homeostasis. It includes two general responses: (a) an acute proinflammatory response resulting from innate immune system recognition of ligands, and (b) an anti-inflammatory response that may serve to modulate the proinflammatory phase and direct a return to homeostasis. This is accompanied by a suppression of adaptive immunity.4 Rather than occurring sequentially, recent data indicate that all three responses are simultaneously and rapidly induced following severe traumatic injury.2

FImage not available.

Schematic representation of the systemic inflammatory response syndrome (SIRS) after injury, followed by a period of convalescence mediated by the counterregulatory anti-inflammatory response syndrome (CARS). Severe inflammation may lead to acute multiple organ failure (MOF) and early death after injury (dark blue arrow). A lesser inflammatory response followed by excessive CARS may induce a prolonged immunosuppressed state that can also be deleterious to the host (light blue arrow). Normal recovery after injury requires a period of systemic inflammation followed by a return to homeostasis (red arrow).1

The degree of the systemic inflammatory response following trauma is proportional to injury severity and is an independent predictor of subsequent organ dysfunction and resultant mortality. Recent work has provided insight into the mechanisms by which immune activation in this setting is triggered. The clinical features of the injury-mediated systemic inflammatory response, characterized by increased body temperature, heart rate, respirations, and white blood cellcount, are similar to those observed with infection (Table 2-1). While significant efforts have been devoted to establishing a microbial etiology for this response, it is now widely accepted that systemic inflammation following trauma is sterile. Although the mechanisms for the sterile response are less well understood, it is likely to result from endogenous molecules that are produced as a consequence of tissue damage or cellular stress, as may occur with hemorrhagic shock and resuscitation.5 Termed alarmins or damage-associated molecular patterns (DAMPs), these effectors, along with the pathogen-associated molecular patterns (PAMPs), interact with specific cell receptors that are located both on the cell surface and intracellularly.6 The best described of these receptors are members of the toll-like receptor family.

Table 2-1Clinical spectrum of infection and systemic inflammatory response syndrome (SIRS)
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Trauma DAMPs are structurally diverse endogenous molecules that are immunologically active. Table 2-2 includes a partial list of DAMPs that are released either passively from necrotic/damaged cells or actively from physiologically “stressed” cells by upregulation or overexpression. Once they are outside the cell, DAMPs promote the activation of innate immune cells, as well as the recruitment and activation of antigen-presenting cells, which are engaged in host defense.7 The best-characterized DAMP with significant preclinical evidence for its release after trauma and with a direct link to the systemic inflammatory response is high-mobility group protein B1 (HMGB1). Additional evidence for the role of DAMP molecules in postinjury inflammation, including mitochondrial proteins and DNA, as well as extracellular matrix molecules, is also presented.

Table 2-2Damage-associated molecular patterns (DAMPs) and their receptors
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High-Mobility Group Protein B1

The best-characterized DAMP in the context of the injury-associated inflammatory response is HMGB1 protein, which is rapidly released into the circulation within 30 minutes following trauma. HMGB1 is highly evolutionarily conserved across species. It was first described as a constitutively expressed, nonhistone chromosomal protein that participated in a variety of nuclear events, including DNA repair and transcription. HMGB1 was also detected in the cytosol and extracellular fluids at low levels, although its function outside the cell was not clear. Subsequent studies have proven, however, that HMGB1 is actively secreted from immune-competent cells stimulated by PAMPs (e.g., endotoxin) or by inflammatory cytokines (e.g., tumor necrosis factor and interleukin-1). This process occurs outside the classic secretory pathway via a mechanism that is independent of endoplasmic reticulum and the Golgi complex. Moreover, recent data indicate that HMGB1 release can be regulated by the inflammasome.8 Stressed nonimmune cells such as endothelial cells and platelet also actively secrete HMGB1. Finally, passive release of HMGB1 can occur following cell death, whether it is programmed or uncontrolled (necrosis).

Once outside the cell, HMGB1 interacts with its putative receptors either alone or in concert with pathogenic molecules to activate the immune response, and in this way, functions as a proinflammatory cytokine. HMGB1 has been shown to signal via the toll-like receptors (TLR2, TLR4, TLR9), the receptor for advanced glycosylation end products (RAGE), CD24, and others. The activation of TLRs mainly occurs in myeloid cells, whereas RAGE is thought to be the receptor target in endothelial and somatic cells. The diverse proinflammatory biologic responses that result from HMGB1 signaling include: (a) the release of cytokines and chemokines from macrophages/monocytes and dendritic cells; (b) neutrophil activation and chemotaxis; (c) alterations in epithelial barrier function, including increased permeability; and (d) increased procoagulant activity on platelet surfaces, among others.9 In particular, HMGB1 binding to TLR4 triggers the proinflammatory cytokine release that mediates “sickness behavior.” This effect is dependent on the highly conserved domain structure of HMGB1 that can be recapitulated by a synthetic 20-amino acid peptide containing a critical cysteine residue at position 106.10

Recent data have explored the role of this cysteine residue, as well as two others that are highly conserved, in the biologic function of HMGB1. They demonstrate that the redox state of the three residues regulates the receptor binding ability of HMGB1 to influence its activity, including cytokine production. For example, a thiol at C106 is required for HMGB1 to promote macrophage tumor necrosis factor (TNF) release. In addition, a disulfide bond between C23 and C45 is also required for cytokine release because reduction of the disulfide linkage or further oxidation will reduce the ability of HMGB1 to function as a cytokine. Therefore, if all three cysteine residues are in reduced form, HMGB1 lacks the ability to bind and signal through TLR4, but gains the capacity to bind to CXCL12 to activate CXCR4 and serve as a chemotactic mediator. Importantly, shifts between the redox states have been demonstrated and indicate that redox state dynamics are important regulators of HMGB1.11

Importantly, HMGB1 levels in human subjects following injury correlate with the Injury Severity Score, complement activation, and an increase in circulating inflammatory mediators such as TNF.12 Unchecked, excessive HMGB1 has the capacity to promote a self-injurious innate immune response. In fact, exogenous administration of HMGB1 to normal animals produces fever, weight loss, epithelial barrier dysfunction, and even death.

A Role for Mitochondrial DAMPs in the Injury-Mediated Inflammatory Response

Mitochondrial proteins and/or DNA can act as DAMPs by triggering an inflammatory response to necrosis and cellular stress. Specifically, the release of mitochondrial DNA (mtDNA) and formyl peptides from damaged or dysfunctional mitochondria has been implicated in activation of the macrophage inflammasome, a cytosolic signaling complex that responds to cellular stress. In support of this idea, plasma mtDNA has been shown to be thousands of times higher in both trauma patients and patients undergoing femoral fracture repair when compared to normal volunteers. Further, direct injection of mitochondria lysates in an animal model caused remote organ damage, including liver and lung inflammation.13 These data suggest that with stress or tissue injury, mtDNA and peptides are released from damaged mitochondria where they can contribute to a sterile inflammatory response. From an evolutionary perspective, given that eukaryotic mitochondria derive from bacterial origin, it would make sense that they retain bacterial features capable of eliciting a strong response that is typically associated with a pathogen trigger. For example, mtDNA is circular and contains hypomethylated CpG motifs that resemble bacterial CpG DNA. It is thus capable of producing formylated peptides, which potently induce an inflammatory phenotype in neutrophils, by increasing chemotaxis, oxidative burst, and cytokine secretion. In addition, the mitochondrial transcription factor A (TFAM), a highly abundant mitochondrial protein, is functionally and structurally homologous to HMGB1. It has also been shown be released in high amounts from damaged cells where it acts in conjunction with mtDNA to activate TLR9 signaling.14

Extracellular Matrix Molecules Act as DAMPs

Recent work has explored the role of extracellular matrix (ECM) proteins in the TLR-mediated inflammatory response that follows tissue injury. These molecules, which are sequestered under normal conditions, can be released in a soluble form with proteolytic digestion of the ECM. Proteoglycans, glycosaminoglycans, and glycoproteins such as fibronectin have all been implicated as key players in the DAMP/TLR interaction. Proteoglycans, in particular, have also been shown to activate the intracellular inflammasomes that trigger sterile inflammation. These molecules, which consist of a protein core with one or more covalently attached glycosaminoglycan chains, can be membrane-bound, secreted, or proteolytically cleaved and shed from the cell surface.

Biglycan is one of the first proteoglycans to be described as a TLR ligand.15 It consists of a protein core containing leucine-rich repeat regions, with two glycosaminoglycan (GAG) side chains (chondroitin sulfate or dermatan sulfate). Although biglycan typically exists in a matrix-bound form, with tissue injury, it is released from the ECM in a soluble form where it interacts with TLR2 or TLR4 to generate an immediate inflammatory response.

Various proinflammatory cytokines and chemokines, including TNF-α and interleukin (IL)-1β, are downstream effector molecules of biglycan/TLR2/4 signaling. Among these, the mechanism of biglycan-mediated autonomous synthesis and secretion of mature IL-1β is unique. Usually, release of mature IL-1β from the cell requires two signals, one which is needed to initiate synthesis (TLR2/4-mediated) and the other to process pro-IL-1β to its mature form (inflammasome-mediated). How is it possible for biglycan to provide both signals? Current evidence indicates that when soluble biglycan binds to the TLR, it simultaneously serves as a ligand for a purinergic receptor, which facilitates the inflammasome activation required for IL-1β processing.16 These data support the idea that DAMP-mediated signals can initiate a robust inflammatory response.

DAMPs Are Ligands for Pattern Recognition Receptors

The inflammatory response that occurs following traumatic injury is similar to that observed with pathogen exposure. Not surprising, surface and cytoplasmic receptors that mediate the innate immune response to microbial infection have been implicated in the activation of sterile inflammation. In support of this idea, genes have been identified that are dysregulated acutely both in response to a microbial ligand administered to human volunteers and in response to traumatic injury in a large patient population.17 The classes of receptors that are important for sensing damaged cells and cell debris are part of the larger group of germline encoded pattern recognition receptors(PRRs). The best-described ligands for these receptors are microbial components, the PAMPs. The PRRs of the innate immune system fall into at least four distinct classes: TLRs, calcium-dependent (C-type) lectin receptors (CLRs), retinoic acid–inducible gene (RIG)-I-like receptors (RLRs), and the nucleotide-binding domain, leucine-rich repeat–containing (NBD-LRR) proteins (NLRs; also nucleotide-binding and oligomerization domain [NOD]-like receptors). Following receptor ligation, intracellular signaling modulates transcriptional and posttranslational events necessary for host defense by coordinating the synthesis and release of cytokines and chemokines to either initiate or suppress the inflammatory response. The best described of these, the TLRs, NLRs, and CLRs, are discussed in the following sections.

Toll-Like Receptors

The TLRs are evolutionarily conserved type 1 transmembrane proteins that are the best-characterized PRRs in mammalian cells. They were first identified in Drosophila, where a mutation in the Toll gene led to its identification as a key component in their immune defense against fungal infection. The first human TLR, TLR4, was identified shortly thereafter. Now, more than 10 human TLR family members have been identified, with distinct ligands that include lipid, carbohydrate, peptide, and nucleic acid components of various pathogens. TLRs are expressed on both immune and nonimmune cells. At first, the expression of TLR was thought to be isolated to professional antigen-presenting cells such as dendritic cells and macrophages. However, mRNA for TLR family members have been detected in most cells of myeloid lineage, as well as natural killer (NK) cells.18 In addition, activation of T cells increases their TLR expression and induces their survival and clonal expansion. Direct engagement of TLR in T-regulatory (Treg) cells promotes their expansion and reprograms them to differentiate into T helper cells, which in turn provides help to effector cells. In addition, B cells express a distinct subset of the TLR family that determines their ability to respond to DAMPs; however, the significance of restricted TLR expression in these cells is not yet clear.

All TLRs consist of an extracellular domain, characterized by multiple leucine-rich repeats (LRRs), and a carboxy-terminal, intracellular toll/IL-1 receptor (TIR) domain. The LRR domains recognize bacterial and viral PAMPs in the extracellular environment (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11) or in the endolysosomes (TLR3, TLR7, TLR8, TLR9, and TLR10). Although the role of TLRs in sepsis has been well described, more recent data indicate that a subset of the TLRs, TLR4 in particular, also recognizes DAMPs released from injured cells and tissues.19 Signal transduction occurs with receptor dimerization and recruitment of cytoplasmic adaptor proteins. These adaptor molecules initiate and amplify downstream signals, resulting in the activation of transcription. The transcription factors, which include nuclear factor-κB (NF-κB), activator protein (AP)-1, and interferon regulatory factor (IRF), bind to regulatory elements in promoters and/or enhancers of target genes leading to the upregulation of a large cohort of genes that include interferon (IFN)-α and IFN-β, nitric oxide synthase 2 (NOS2A), and TNF, which play critical roles in initiating innate immune responses to cellular injury and stress. Given the importance of TLR triggering of the innate immune response to immune homeostasis, it is no surprise that the process is tightly regulated. TLR expression is significantly increased following blunt traumatic injury. Further, TLR signaling is controlled at multiple levels, both posttranscriptionally via ubiquitination, phosphorylation, and microRNA actions that affect mRNA stability, as well as by the localization of the TLRs and their signaling complexes within the cell.

Nucleotide-Binding Oligomerization Domain-Like Receptor Family

The NLRs are a large family of proteins composed of intracellular PRRs that sense both endogenous (DAMPs) and exogenous (PAMPs) molecules to trigger innate immune activation. The best characterized of the NLRs is the NLR family pyrin domain-containing 3 (NLRP3), which is highly expressed in peripheral blood leukocytes. It forms the key “sensing” component of the larger, multiprotein inflammasome complex, which is composed of NLRP3; the adapter protein apoptosis-associated speck-like protein containing a CARD (ASC); and the effector protein, caspase 1.20 In the cytoplasm, the receptor resides in an inactive form due to an internal interaction between two adjacent and highly conserved domains. In conjunction with a priming event, such as mitochondrial stress, phagocytosed DAMPs can be sensed by NLRP3, resulting in the removal of the self-repression. The protein can then oligomerize and recruit other complex members. The net result is the autoactivation of pro-caspase 1 to caspase 1. The NLRP3 inflammasome plays a central role in immune regulation by initiating the caspase 1–dependent processing and secretion of the proinflammatory cytokines IL-1β and IL-18. In fact, NLRP3 is the key protein in the mechanism by which IL-1β production is regulated in macrophages. NLRP3 inflammasome activity is tightly regulated by cell-cell interactions, cellular ion flux, and oxidative stress in order to maintain a balanced immune response to danger signals.

While the role of the NLRP3 inflammasome in the sterile inflammatory response following trauma has not been well described, recent evidence suggests that genetic variations in the NLRP3 gene might affect the magnitude of immune inflammatory responses following trauma. Single nucleotide polymorphisms within the NLRP3 gene were found to be associated with increased risk of sepsis and multiple organ dysfunction syndrome in patients with major trauma.21 In an animal model of burn injury, early inflammasome activation has been detected in a variety of immune cells (NK cells, CD4/CD8 T cells, and B cells), as determined by the assessment of caspase 1 cleavage by flow cytometry.22 Further, inhibition of caspase 1 activity in vivo results in increased burn mortality, suggesting that inflammasome activation may play an unanticipated protective role in the host response to injury that may be linked to increased production of specific cytokines. In addition to the NLRP3 inflammasome, there are numerous other NLRP sensors that are capable of detecting a diverse range of molecular targets. Among them are those endogenous molecules that are released as a consequence of tissue injury and cellular stress (hypoxia/hypoperfusion).

C-Type Lectin Receptors

Macrophages and dendritic cells possess receptors that detect molecules released from damaged or dying cells in order to retrieve and process antigens from cell corpses for T-cell presentation. A key family of receptors that directs this process is the CLR family that includes the selectin and the mannose receptor families and that binds carbohydrates in a calcium-dependent fashion. Best described for their sensing of PAMPs, particularly fungal antigens, the CLRs can also act to promote the endocytosis and clearance of cell corpses. More recent work has demonstrated, however, that a subset of CLR receptors such as dendritic cell-NK lectin group receptor-1 (DNGR-1) and macrophage-inducible C-type lectin receptor (Mincle) recognize DAMPS of intracellular origin, such as F-actin and the ribonucleoprotein SAP-130.23 Ligation and activation of Mincle promotes its interaction with an Fcγ receptor, which contains immunoreceptor tyrosine-based activation motifs. This leads to proinflammatory cytokine, chemokine, and nitric oxide production, in addition to neutrophil recruitment. In this way, Mincle may contribute to local inflammation at sites of tissue injury.

Soluble Pattern Recognition Molecules: The Pentraxins

Soluble pattern recognition molecules (PRMs) are a molecularly diverse group of molecules that share a conserved mode of action that is defined by complement activation, agglutination and neutralization, and opsonization. The best described of the PRMs are the pentraxins. PRMs can be synthesized at sites of injury and inflammation by macrophages and dendritic cells, while neutrophils can store PRMs and can release them rapidly following activation. In addition, epithelial tissues (the liver in particular) serve as a reservoir source for systemic mass release. The short pentraxin, C-reactive protein (CRP), was the first PRM to be identified. Serum amyloid protein (SAP), which has 51% sequence similarity to human CRP, also contains the pentraxin molecular signature. CRP and SAP plasma levels are low (≤3 mg/L) under normal circumstances. However, CRP is synthesized by the liver in response to IL-6, increasing serum levels more than a 1000-fold. Thus, CRP is considered part of the acute-phase protein response in humans. For this reason, CRP has been studied as a marker of the proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis. CRP and SAP are ancient immune molecules that share many functional properties with antibodies: they bind bacterial polysaccharides, ECM components, apoptotic cells, and nuclear materials, as well as all three classes of Fcγ receptors (FcγR). Both molecules also participate in the activation and regulation of complement pathways. In this way, short pentraxins can link immune cells to the complement system.24

Finally, significant data support a role for pentraxin 3 (PTX3), a long pentraxin family member, in the “sterile” inflammatory response associated with cellular stress. While CRP is produced solely in the liver, PTX3 is produced by various cells in peripheral tissues, including immune cells. PTX3 plasma concentrations increase rapidly in various inflammatory conditions, including sepsis. Further, in a recent prospective study of polytraumatized patients, serum PTX3 concentrations were highly elevated, peaking at 24 hours. In addition, PTX3 concentrations at admission were associated with injury severity, whereas higher PTX3 serum concentrations 24 hours after admission correlated with lower probability for survival.25

Pattern Recognition Receptor Signaling: Toll-Like Receptors and the Inflammasome

As noted earlier, members of the TLR family respond to endogenous molecules released from damaged or stressed cells. In animal models, activation of TLRs in the absence of bacterial pathogens correlates with the development of critical illness including “sterile inflammation.” What we know about TLR signaling events has largely been derived from the TLR-mediated response to bacterial pathogens. However, it is likely that the intracellular adaptors required for signal transmission by TLRs in response to exogenous ligands are conserved and used for “damage” sensing of endogenous (“self”) ligands as well. The intracellular domain structure of TLRs is highly conserved and is characterized by a cytoplasmic toll/IL-1R homology (TIR) domain. Binding of ligand to the receptor results in a receptor dimer, either a homodimer (e.g., TLR4/TLR4) or heterodimer (e.g., TLR2/TLR1), which recruits a number of adaptor proteins to the TIR domains, through TIR-TIR interaction.26 With one exception (TLR3), the universal adaptor protein central to the TLR signaling complex is myeloid differentiation factor 88 (MyD88), a member of the IL-1 receptor subfamily. MyD88 works through the recruitment of a second TIR-containing adaptor, MyD88 adaptor-like protein (Mal), in the context of TLR4 and TLR2 signaling, which serves as a bridge between MyD88 and activated TLRs to initiate signal transduction. It is interesting that Mal’s adaptor function requires cleavage of the carboxy-terminal portion of the protein by caspase 1, a key effector of the inflammasome.27 This finding suggests an important synergy between TLRs and NLRs that may potentiate TLR-mediated signaling. There are three other TIR domain-containing adaptor proteins that are also important to TLR-signaling events; these are TIR-domain-containing adapter-inducing INF-β (TRIF), TRIF-related adaptor molecule (TRAM), and sterile α- (SAM) and HEAT/armadillo (ARM) motif-containing protein (SARM). Two of these, TRIF and TRAM, are involved in the MyD88-independent signaling pathways, which are activated by TLR3 and TLR4.

Signaling through the MyD88-dependent pathway results in the activation of numerous cytoplasmic protein kinases including IL-1 receptor–associated kinases (IRAK-1 and IRAK-4), resulting in an interaction with TNF receptor–associated factor 6 (TRAF6). TRAF6, an E3 ubiquitin ligase, forms a complex with two other proteins, which together activate the complex that subsequently phosphorylates IκB kinase (IKK)-β and the MAP kinases (MAPKs). Ultimately, the phosphorylation of IκB by the IKK complex and NEMO (NF-κB essential modulator) leads to its degradation, which frees NF-κB and allows its translocation to the nucleus and the transcription of NF-κB target genes. Simultaneously, MAPK activation is critical for activation of the activator protein-1 (AP-1) transcription factor, and thus production of inflammatory cytokines. The MyD88-independent pathway acts through TRIF to activate NF-κB, similar to the MyD88-dependent pathway. However, TRIF can also recruit other signaling molecules to phosphorylate interferon-regulatory factor 3 (IRF3), which induces expression of type I IFN genes.26

Signaling from the Inflammasome

As discussed earlier, activation and assembly of the inflammasome in response to DAMP sensing result in the cleavage of pro-caspase 1 into two products. This event is pivotal to all known inflammasome signaling pathways. The caspase 1 products assemble to form the IL-1 converting enzyme (ICE), which cleaves the IL-1 cytokines, IL-1β, IL-18, and IL-33. This final step is required for activation and secretion of the cytokines from the cell.20 IL-1β and IL-18 are potent proinflammatory cytokines that promote key immune responses that are essential to host defense. Thus, the synthesis, processing, and secretion of these cytokines are tightly regulated, as successful cytokine release requires a two-step process. The first signal, which is typically TLR-mediated, initiates the synthesis and storage of the inactive cytokine precursors in the cytoplasm. The second signal, which is inflammasome-mediated, initiates proteolytic cleavage of the procytokine, which is a requirement for its activation and secretion from the cell. Of further interest, evidence has demonstrated that both IL-1β and IL-18 lack a signal sequence, which is usually necessary for those proteins that are destined for cellular export. These signal peptides target proteins to the endoplasmic reticulum (ER) and to the Golgi complex, where they are packaged for secretion from the cell through the classical secretory pathway. More than 20 proteins in addition to IL-1β and IL-18 undergo unconventional protein secretion independent of the ER and Golgi complex.28 The list includes signaling molecules involved in inflammatory, cell survival, and repair responses, such as HMGB1, IL-1α, galectins 1 and 3, and FGF2. Currently, the mechanisms responsible for unconventional protein secretion are not understood; however, the process is also evident in yeast under conditions of cellular stress. It makes evolutionary sense that a mechanism for rapid secretion of stored proteins essential to the stress response is highly conserved.

 

recent work indicates that the CNS receives information with regard to injury-induced inflammation both via soluble mediators as well as direct neural projections that transmit information to regulatory areas in the brain (Fig. 2-2). How does the CNS sense inflammation? DAMPs and inflammatory molecules convey stimulatory signals to the CNS via multiples routes. For example, soluble inflammatory signaling molecules from the periphery can reach neurons and glial cells directly through the fenestrated endothelium of the circumventricular organs (CVO) or via a leaky blood brain barrier in pathologic settings such as may occur following a traumatic brain injury.29 In addition, inflammatory stimuli can interact with receptors located on the brain endothelial cells to generate a variety of proinflammatory mediators (cytokines, chemokines, adhesion molecules, proteins of the complement system, and immune receptors) that directly impact the brain parenchyma. Not surprising, this response is countered by potent anti-inflammatory signaling, a portion of which is provided by the hypothalamic-pituitary-adrenal (HPA) axis and the release of systemic glucocorticoids. Inflammatory stimuli in the CNS result in behavioral changes, such as increased sleep, lethargy, reduced appetite, and the most common feature of infection, fever.

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The responses are:

 

The sympathoadrenal response results from an increased secretion of catecholamines from the adrenal medulla. Circulating norepinephrine and epinephrine result in tachycardia and hypertension, and directly modify the function of numerous organs, including the liver, pancreas, and kidney.

 

 

 

    The overall metabolic effect is increased catabolism, which mobilizes substrate to provide energy, and retention of salt and water to maintain fluid volume and cardiovascular homeostasis.

 

This response includes the elaboration of adrenocortical hormones, catecholamines, and glucagon; a decrease in insulin release resulting in hyperglycemia; and the secretion of antidiuretic hormone (ADH) and aldosterone, as well as the release of cytokines and the stimulation of a hypercoagulable state.

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the stimulation of a hypercoagulable state.

The innate immune system to produce a systemic inflammatory response in an attempt to limit damage and to restore homeostasis. It includes two general responses:

(a) an acute proinflammatory response resulting from innate immune system recognition of ligands

Immunologic activation includes the production of cytokines and acute phase reactants, and resultant neutrophil release and demargination, and lymphocyte proliferation

an increase in cytokine production and acute phase reactants. Cytokines are a group of low-molecular-weight proteins that include the interleukins and interferons, and they have a major role in the body's response to surgery and trauma. They are responsible for local effects of mediating and maintaining the inflammatory response to tissue injury. The main cytokines released after surgery are interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6. The initial reaction of the body to surgery is to generate TNF-α and IL-1 from activated macrophages and monocytes in damaged tissues. This in turn stimulates the production of IL-6, the main cytokine responsible for the systemic changes known as the acute phase response. Cytokine production reflects the degree of tissue trauma; levels are lowest in laparoscopic and minimally-invasive procedures, and highest in major vascular procedures, joint replacements, and colorectal surgery. Cytokine levels peak 24-hours postoperatively and remain elevated for two to three days.

Acute Phase Response

The acute phase response is characterized by systemic changes including fever, granulocytosis, and the production of acute phase proteins in the liver. Acute phase proteins, including Creactive protein (CRP), fibrinogen, and α-2 macroglobulin, are inflammatory mediators, antiproteinases, and scavengers in tissue repair. D-dimer protein, a fibrin degradation product, will also be elevated in the postoperative period and may remain elevated for several weeks. Hematologic changes also occur along with the acute phase reaction, resulting in neutrophil leukocytosis and lymphocyte proliferation. Fever and leukocytosis can be expected in the first 48 hours after surgery, and should not prompt an infectious workup or antibiotic treatment in most cases.

(b) an anti-inflammatory response that may serve to modulate the proinflammatory phase and direct a return to homeostasis.

Image not available.

 

Schematic representation of the systemic inflammatory response syndrome (SIRS) after injury, followed by a period of convalescence mediated by the counterregulatory anti-inflammatory response syndrome (CARS). Severe inflammation may lead to acute multiple organ failure (MOF) and early death after injury (dark blue arrow). A lesser inflammatory response followed by excessive CARS may induce a prolonged immunosuppressed state that can also be deleterious to the host (light blue arrow). Normal recovery after injury requires a period of systemic inflammation followed by a return to homeostasis (red arrow). (from Guirao X, Lowry SF. Biologic control of injury and inflammation: Much more than too little or too late. World J Surg. 1996;20:437.

This is accompanied by a suppression of adaptive immunity.4 Rather than occurring sequentially, recent data indicate that all three responses are simultaneously and rapidly induced following severe traumatic injury.2

 

The degree of the systemic inflammatory response following trauma is proportional to injury severity and is an independent predictor of subsequent organ dysfunction and resultant mortality. Recent work has provided insight into the mechanisms by which immune activation in this setting is triggered. The clinical features of the injury-mediated systemic inflammatory response, characterized by increased body temperature, heart rate, respirations, and white blood cellcount, are similar to those observed with infection (Table 2-1). While significant efforts have been devoted to establishing a microbial etiology for this response, it is now widely accepted that systemic inflammation following trauma is sterile. Although the mechanisms for the sterile response are less well understood, it is likely to result from endogenous molecules that are produced as a consequence of tissue damage or cellular stress, as may occur with hemorrhagic shock and resuscitation.5Termed alarmins or damage-associated molecular patterns (DAMPs), these effectors, along with the pathogen-associated molecular patterns (PAMPs), interact with specific cell receptors that are located both on the cell surface and intracellularly.6 The best described of these receptors are members of the toll-like receptor family.

 

 

 

Increased corticotrophin stimulates cortisol secretion from the adrenal cortex resulting in increased blood glucose levels, argininevasopressin stimulates the kidney to retain water, and insulin secretion by the pancreas is often diminished.

Growth hormone Increases

 

Thyroid Stimulating Hormone May increase or decrease

 

Follicle Stimulating Hormone May increase or decrease

 

Leutinizing Hormone May increase or decrease

 

 

 

 

Antidiuretic Hormone (or Vasopressin, also known as arginine vasopressin (AVP), or argipressin) increases

Blood loss, pain related to surgical incisions, fasting prior to surgery, nausea or vomiting, and various drug administrations are only a few of the factors that predispose the surgical patient to release of ADH and aldosterone. The resulting sodium and water retention make it very difficult to monitor the state of hydration of the patient by relying entirely on urine volumes, since these hormones tend to decrease urine output in spite of normovolemia. Other indices of adequacy of perfusion, such as level of consciousness, capillary return, skin warmth, pulse, and blood pressure need to be assessed. In addition, the syndrome of inappropriate ADH release (SIADH) is relatively common in the postoperative period, placing patients at risk of water intoxication and severe hyponatremia when even modest water loads are administered. These problems can be largely avoided if treatment is guided by frequent routine monitoring of electrolytes and fluid volume status.

 

The syndrome of inappropriate ADH release (SIADH) is relatively common in the postoperative period, placing patients at risk of water intoxication and severe hyponatremia when even modest water loads are administered. These problems can be largely avoided if treatment is guided by frequent routine monitoring of electrolytes and fluid volume status.

 

 
Usually small increases

Causing hyperglycemia

 

 

Often decreases resulting in hyperglycemia.

Hyperglycemia may occur in a patient who has previously demonstrated no evidence of abnormality in glucose levels. This situation may also unmask a latent diabetic state in some patients, as well as complicating the management of already established diabetes mellitus in the critically ill surgical patient. Close monitoring of blood glucose, ketones, electrolytes, and acid-base status is essential for proper management of the surgical patient.

 

Cortisol Increases

Cortisol secretion increases rapidly following the start of surgery. It results in protein breakdown, gluconeogenesis in the liver, and in-creased lipolysis. Blood glucose concentrations increase and are related to the intensity of the surgical injury. Consequently, longer and more drastic elevations in blood glucose are seen in cardiac surgery than in minor surgical procedures such as herniorrhaphy. The usual mechanisms that maintain glucose homeostasis are ineffective in the postoperative period; cortisol promotes glucose production, there is a relative lack of insulin, and increased peripheral insulin resistance. Glycemic control is very important in surgical patients as the risks of perioperative hyperglycemia are well documented and include wound infection and impaired wound healing.

Protein catabolism is an important effect of increased perioperative cortisol concentrations. Both skeletal and visceral muscle are broken down to release amino acids for energy or to be used by the liver to form new protein including the acute phase reactants. This process results in weight loss, muscle wasting, and impaired healing. Studies have shown that surgical patients provided with nutritional supplements including glutamine and arginine, two essential amino acids, benefited from a faster recovery, fewer infections, and a shorter hospital stay.

 

Aldosterone Increases

 

 
Catecholamines Increases

 

 

     
   
  Thyroxine Decrease

 

 

 

Acute fluid and electrolyte shifts may occur, the renal response to volume infusion may be altered, and the catabolic response results in a phase of negative nitrogen balance. All these responses vary in intensity, depending on the magnitude and duration of the injury, the adequacy of resuscitation, and the presence of complications such as hemorrhage and sepsis. The increase in metabolic rate increases oxygen requirement and consumption.

 


 

4) Third-Space Fluid Sequestration

Following surgical trauma, occult fluid loss may occur at several sites, including the area of injury, where extravascular fluid may accumulate in the interstitial and intracellular spaces,as well as in the retroperitoneal space during intra-abdominal manipulation. In addition, operations involving the gastrointestinal (GI) tract or abnormalities resulting from surgical diseases such as peritonitis may result in decreased motility of the gut and sequestration of large volumes of fluid within the gut lumen, the gut wall, and the entire large surface area of the peritoneal cavity. This type of fluid depletes circulating blood volume and is not easily measured by most available clinical methods. In the patient with compromised cardiorespiratory reserve, close titration of fluid balance is crucial. In such patients, central hemodynamic monitoring may be required in addition to other clinical indices of normal perfusion and volume status.

5) Hypercoagulable State

The hypercoagulable state resulting from surgical trauma necessitates the institution of either pharmacological and/or mechanical thromboprophylaxis depending on the individual patient risk of bleeding as soon as possible. It is important to recognize that virtually every surgical patient is at risk for thromboembolic disease, and some are at extraordinarily high risk. Pharmacological prophylactic regimens pose a minor risk of bleeding, but can be employed in most surgical patients.

Acute fluid and electrolyte shifts may occur, the renal response to volume infusion may be altered, and the catabolic response results in a phase of negative nitrogen balance.11,12 All these responses vary in intensity, depending on the magnitude and duration of the injury, the adequacy of resuscitation, and the presence of complications such as hemorrhage and sepsis. The increase in metabolic rate increases oxygen requirement and consumption. The management implications of these responses to surgical stress are outlined in the following sections.

 

The inflammatory response to injury occurs as a consequence of the local or systemic release of “damage-associated” molecules, which use similar signaling pathways to mobilize the necessary resources required for the restoration of homeostasis. Minor host insults result in a localized inflammatory response that is transient and in most cases beneficial. Major host insults, however, may lead to amplified reactions, resulting in systemic inflammation, remote organ damage, and multiple organ failure in as many as 30% of those who are severely injured.

Recent data support this idea and suggest that severely injured patients who are destined to die from their injuries differ from survivors only in the degree and duration of their dysregulated acute inflammatory response.1,2

[relevant because systemic inflammation is a central feature3 of both sepsis and severe trauma. Understanding the complex pathways that regulate local and systemic inflammation is necessary to develop therapies to intervene during overwhelming sepsis or after severe injury. Sepsis, defined by a systemic inflammatory response to infection, is a disease process with an incidence of over 900,000 cases per year. Further, trauma is the leading cause of mortality and morbidity for individuals under age 45.}

what is known about the soluble and cellular effectors of the injury-induced inflammatory response; how the signals are sensed, transduced, and modulated; and how their dysregulation is associated with immune suppression. We will also discuss how these events are monitored and regulated by the central nervous system. Finally, we will review how injury reprograms cellular metabolism, in an attempt to mobilize energy and structural stores to meet the challenge of restoring homeostasis.


[ as well as the release of cytokines and the stimulation of a hypercoagulable state.]

Acute fluid and electrolyte shifts may occur, the renal response to volume infusion may be altered, and the catabolic response results in a phase of negative nitrogen balance.11,12 All these responses vary in intensity, depending on the magnitude and duration of the injury, the adequacy of resuscitation, and the presence of complications such as hemorrhage and sepsis. The increase in metabolic rate increases oxygen requirement and consumption.

Endogenous damage-associated molecular patterns (DAMPs) are produced following tissue and cellular injury. These molecules interact with immune and nonimmune cell receptors to initiate a systemic inflammatory response following severe traumatic injury.


MAGNITUDE AND DURATION OF SURGICAL INSULT

The duration and magnitude of surgical procedures affect the intensity of the metabolic and endocrine response. The aim should be to decrease the magnitude, duration, and frequency of surgical insults to the critically ill patient, particularly patients with poor nutritional and cardiorespiratory reserve. This goal must be considered in the context of the underlying problem. The magnitude and duration of the surgical procedure should not be minimized at the expense of incomplete eradication of a surgical lesion, such as a source of sepsis, since failure to eradicate the septic focus would lead to further complications, such as respiratory failure and dependence on mechanical ventilation in the ICU.

In the setting of the multiply injured patient requiring massive blood transfusions that can lead to hypothermia, coagulopathy, and severe cardiorespiratory and renal compromise, “damage-control laparotomy” or abbreviated laparotomy should be considered. This consists of rapid control of hemorrhage (by ligation of vessels and packing) and removal of gross contamination followed by temporary closure, which should be followed as soon as possible by more definitive procedures as improvement in the patient’s condition in the ICU allows.

New Frontier: methrexate in controling inflammatory resposne.

 

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